Cannabinoid exposure decreases host resistance to viral and bacterial infections in animals, but the pertinent aspect of immunity impaired by cannabinoids is unclear. Helper T cells are regulatory cells affecting all forms of immunity by cytokines. An important function of macrophages is to deliver signals to T cells for their activation by way of co- stimulatory molecules. Disruption of macrophage co-stimulation results in compromised in T cell immunity and could contribute to enhanced pathogenic infectivity. The proposal will investigate the hypothesis that cannabinoids inhibit macrophage function by down-regulating co- stimulatory molecules resulting in defective T cell competency. We found that delta9-tetrahydoircannabinol (THC) impairs co-stimulatory activity of wild-type peritoneal macrophages, but not cells from mice genetically deficient in the peripheral CB2 receptor. Defective co-stimulation of a macrophage cell line caused by THC was due to decreased expression of CD24, a co-stimulatory molecule. Participation of a cannabinoid receptor in decreased expression of co-stimulatory molecules will be determined by examining possible reversal of THC's effects by receptor-selective antagonists and the impact of CB2 receptor-selective ligands on wild-type macrophages, and possible lack of THC-induced down-regulation for macrophages from CB2 deficient mice. To examine whether endogenous cannabinoids have a role in immune homeostasis, the influence of anandamide on macrophage costimulatory activity and molecular expression will be determined. Contribution of the signal transduction pathway via G protein-coupled cannabinoid receptors will be determined by agents that circumvent the signalling activities of Gi/o subunits. The mechanism by which THC decreases CD24 expression will be determined by examining the steps in protein expression ranging from mRNA transcription to protein cleavage from the plasma membrane. Finally, the impact of THC on co-stimulatory molecules expressed by macrophage-like microglial cells in the brain, which have an important role in host defense in the central nervous system, will be determined. As a result of in vivo THC exposure, an association between down- regulation of co-stimulatory molecules in the brain and decreased host resistance to a pathogen that localizes to the brain will be determined.